title: LBH589 Inhibits proliferation and metastasis of hepatocellular carcinoma via inhibition of gankyrin/STAT3/Akt pathway.
abstract: BACKGROUND
  Gankyrin has shown to be overexpressed in human liver cancers and plays a complex role in hepatocarcinogenesis. Panobinostat (LBH589), a new hydroxamic acid-derived histone deacetylase inhibitor has shown promising anticancer effects recently. Here, we investigated the potential of LBH589 as a form of treatment for hepatocellular carcinoma (HCC).
  
  
  METHODS
  Gankyrin plasmid was transfected into HCC cells, and the cells were selected for more than 4 weeks by incubation with G418 for overexpression clones. The therapeutic effects of LBH589 were evaluated in vitro and in vivo. Cell proliferation, apoptosis, cell cycle, invasive potential, and epithelial-mesenchy-mal transition (EMT) were examined.
  
  
  RESULTS
  LBH589 significantly inhibited HCC growth and metastasis in vitro and in vivo. Western blotting analysis indicated that LBH589 could decrease the expression of gankyrin and subsequently reduced serine-phosphorylated Akt and tyrosine-phosphorylated STAT3 expression although the total Akt and STAT3 were unaffected. LBH589 inhibited metastasis in vitro via down-regulation of N-cadherin, vimentin, TWIST1, VEGF and up-regulation of E-cadherin. LBH589 also induced apoptosis and G1 phase arrest in HCC cell lines. Ectopic expression of gankyrin attenuated the effects of LBH589, which indicates that gankyrin might play an important role in LBH589 mediated anticancer effects. Lastly, in vivo study indicated that LBH589 inhibited tumor growth and metastasis, without discernable adverse effects comparing to control group, with abrogating gankyrin/STAT3/Akt pathway.
  
  
  CONCLUSIONS
  Our results suggested that LBH589 could inhibit HCC growth and metastasis through down-regulating gankyrin/STAT3/Akt pathway. LBH589 may present itself as a novel therapeutic strategy for HCC.
authors.affiliation: Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, 150001 Harbin, Heilongjiang Province, China. san3mudeepwhite@163.com.
authors.forename: Xuan
authors.initials: X
authors.lastname: Song
authors.forename: Jiabei
authors.initials: J
authors.lastname: Wang
authors.forename: Tongsen
authors.initials: T
authors.lastname: Zheng
authors.forename: Ruipeng
authors.initials: R
authors.lastname: Song
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Liang
authors.forename: Nishant
authors.initials: N
authors.lastname: Bhatta
authors.forename: Dalong
authors.initials: D
authors.lastname: Yin
authors.forename: Shangha
authors.initials: S
authors.lastname: Pan
authors.forename: Jiaren
authors.initials: J
authors.lastname: Liu
authors.forename: Hongchi
authors.initials: H
authors.lastname: Jiang
authors.forename: Lianxin
authors.initials: L
authors.lastname: Liu
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000556:secondary; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D000077767:Panobinostat; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051020:bcl-X Protein; D000077767:Panobinostat; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D046988:Proteasome Endopeptidase Complex